Primary lateral sclerosis (PLS) is a rare neurological disorder due to degeneration of tracts that connect neurons originating in the brain's cortex to motor neurons in the brainstem and spinal cord. Except for an extremely rare genetic form (Yang et al 2002), its causes are not known and its treatments are marginally effective. Diagnosis of PLS has been a subject of much debate over the years because the signs and symptoms of PLS may be seen in other disorders as well, particularly amyotrophic lateral sclerosis (ALS), the spastic parapareses (SP) and multiple sclerosis (MS). Although several sets of diagnostic criteria have been proposed (Charcot 1865, Stark and Moersch 1945, Pringle et al 1992, Brooks 1994), none were developed as the result of consensus among practitioners and researchers with expertise in sub-specialties to each contribute unique knowledge and apply current technologies to defining this disease. Additionally, present criteria are loosely and quite often inaccurately applied, even by neurologists, producing a confusing and frustrating experience for patients, and making meaningful clinical research impossible. Our long-term goal is to accurately identify PLS patients so meaningful clinical research can be undertaken to establish the cause(s) of PLS and develop effective treatments. As a first step, we plan to convene a group of 50-100 neuroscientists, on June 4-6, 2004 at the Chaminade Resort, Santa Cruz, CA, with expertise in clinical neurology, imaging, neuropathology, genetics and neurophysiology to accurately define PLS and chart areas for meaningful research. Our specific aims are (1) To define Primary lateral sclerosis (PLS) by: clinical, neurophysiological, imaging, neuropathological, and genetic criteria. (2) Delineate the relationship and differences between PLS and ALS, SP, and other spasticity causing diseases. (3) Establish future directions for PLS in clinical research, mouse models, and molecular-based research. (4) Publish a summary of the conference proceeding and consensus criteria for delineating PLS as a specific entity and its relationship to other motor neuron disorders in a major journal.